Which antiretroviral regimen is associated with
higher adherence in Brazil? A comparison of
single, multi, and dolutegravir-based regimens
Qual esquema antirretroviral está associado à
maior adesão no Brasil? Uma comparação dos
esquemas de comprimido único, múltiplos
comprimidos e com dolutegravir
¿Qué tratamiento antirretroviral está asociado con
adherencia más alta en Brasil? Una comparación
de tratamientos únicos, múltiples y basados
en el dolutegravir
Tarsilla Spezialli Cardoso 1 Juliana de Oliveira Costa 1 Edna Afonso Reis 1 Micheline Rosa Silveira 1 Palmira de Fátima Bonolo 1 Simone Furtado dos Santos 1 Maria das Graças Braga Ceccato 1
Abstract
We evaluated adherence to highly active antiretroviral therapy (HAART) and its associated factors according to the type of regimen in patients initiat-ing treatment in Belo Horizonte, Minas Gerais State, Brazil. We measured adherence using the eight items Morisky Therapeutic Adhesion Scale (MMAS-8) and compared the use of “backbone” tenofovir/lamivudine plus efavirenz one tablet daily (STR) or dolutegravir in multi-tablet once-daily (MTR-DTG), or other multi-tablet regimens (MTR-other). We conduct-ed a multivariate logistic regression analysis to address factors associatconduct-ed with adherence. A total of 393 patients were included, 254 used STR, 106 MTR-DTG, and 33 MTR-other. The overall adhesion rate was 44.8% (95%CI: 39.4; 50.1), 50% for MTR-DTG, 43.3% for STR and 39.4% for MTR-other. Mul-tivariate analysis showed a higher chance of adherence among patients us-ing MTR-DTG, those who received and understood counselus-ing about their treatment and with a higher quality of life. Prior use of illicit drugs in the lifetime was associated with poorer adherence. Overall adherence was low, highlighting the need for strategies focusing on counseling about medicines and substance use. Pill burden was not an issue for patients using MTR-DTG once-daily, who achieved better results.
HIV; Anti-retroviral Agents; Medication Adherence; Self Report
Correspondence J. O. Costa
Universidade Federal de Minas Gerais.
Av. Prof. Alfredo Balena 190, Belo Horizonte, MG 30130-100, Brasil.
julianaoc@far.grad.ufmg.br
1 Universidade Federal de Minas Gerais, Belo Horizonte, Brasil.
doi: 10.1590/0102-311X00115518
Introduction
The therapeutic success of highly active antiretroviral therapy (HAART) is assessed by viral suppres-sion and its achievement requires high levels of HAART adherence, generally 95% 1,2. Lower levels of
adherence may lead to therapeutic failure, viral mutations selection and the development of resistance to medicines 3,4.
Adherence is a worldwide challenge and is associated with several factors related to the individual, to the medicines and to the health services. Major difficulties with HAART occur at the beginning of the treatment when the main factors affecting adherence are adverse reactions, number of tablets administered, level of schooling, the presence of AIDS symptoms, among others directly influencing the individual’s routine 5,6.
Simplification of HAART is a worldwide trend as a strategy to increase the adherence and include the use of single tablet regimens (STR) consisting of two or more drugs in a single tablet, the use of single daily regimens, and the use of medicines with lower toxicity 7.
Previous studies have reported greater adherence to HAART for patients using STR containing tenofovir (TDF), emtricitabine (FTC) and efavirenz (EFV) 3,7,8. In Brazil, the generic STR is available to the population since 2015, however, it contains a different formulation: TDF, lamivudine (3TC) and EFV 4. In 2017, dolutegravir (DTG) was included in the first-line regimen for individuals initiating
HAART, replacing EFV 4. This regimen includes one tablet containing TDF/3TC plus one DTG tablet,
administered once-daily. However, the impact of different administration regimens in the adherence to HAART is still unknown.
The scarcity of observational studies in HAART-naïve individuals specifically evaluating the STR containing TDF/3TC/EFV or the TDF/3TC + DTG regimen, associated to the updating of the Brazilian guidelines, highlights the need to evaluate the adherence to the regimens available to the population.
Brazil has been recognized for its strong response to the HIV epidemic. The Federal government has provided since the early 1990s generic versions of antiretroviral drugs, and, it started providing in 2013 public antiretroviral treatment to all HIV-adults seeking care, regardless of the stage of HIV they were facing. Despite of the struggle for sustainable financing of the Brazilian Unified National Health System (SUS), Brazil’s national HIV and AIDS response is integrated into the country’s Health Strategic Plan. The approach to HIV prevention involves promoting and improving access to HIV testing, immediate treatment for those testing positive regardless of CD4 count, and the provision of pre- and post-exposure prophylaxis 4.
Primary care in SUS expanded its services to 64% of the national population in addition to the other HIV/AIDS public services, 655 reference services, 25 laboratories for HIV-1 diagnostic, 12 ser-vices to lipodystrophy treatment, and, 101 Centers for Testing and Counseling 4.
Accordingly, we aimed to evaluate the adherence to first-line antiretroviral regimens and associ-ated factors among individuals initiating treatment in Southeast Brazil to contribute in developing target strategies to improve patient’s outcomes.
Methods
This is a baseline cross-sectional analysis of the ECOART cohort study conducted in Belo Horizonte, capital of Minas Gerais State, Brazil. We evaluated people living with HIV with at least seven and maximum 180 days of HAART usage, selected by non-randomized sampling and identified through their register on the Medication Logistics Control System (SICLOM).
Patients were recruited from September 2015 to August 2017 in three public reference services in outpatient HIV care covering about 80% of people living with HIV in the city, according to regis-ters from the SICLOM. Service I belongs to a large hospital of the public network of Minas Gerais that provides specialized assistance with interdisciplinary care and dispensing of medication to the patient. Service II is a specialized municipal outpatient assistance and also a testing and counseling center that provides comprehensive and interdisciplinary treatment and dispensing of medicines.
Service III is also a municipal reference, and provides interdisciplinary assistance, integral and dis-pensing of medicines.
Inclusion criteria were individuals aged 13+ years old, attending one of the three reference ser-vices during the recruitment period, who had a minimum autonomy to answer the interview, agreed to participate in the study and signed the consent form. We obtained data through face-to-face inter-views with eligible patients and complemented with national data from the Laboratory Test Control System (SISCEL) and SICLOM electronic systems from the Brazilian Ministry of Health.
The research was conducted in accordance with the Resolution n. 466/2012 of the Brazilian Nation-al HeNation-alth Council. All data collected were kept confidentiNation-al and the identification of individuNation-als was preserved. For the accomplishment of the research, we obtained the approval of the Ethics Research Committee of Minas Gerais Federal University (UFMG; CAAE-31192914.3.0000.5149) and of the participating centers.
Events and explanatory variables
Adherence (the dependent variable) was measured by self-report using the eight items Morisky
Thera-peutic Adhesion Scale (MMAS-8) 9,10,11 validated in Brazil 12. Scores ranged from 0 to 8 points and
patients who obtained 8 points (100%) were considered adherents. Independent variables were: (i) sociodemographic: sex, age, schooling level, own income, employment status, economic class, marital status; (ii) behavioral and habits of life: alcohol use, cigarette smoking, illicit drugs use in lifetime, condoms usage in the last month, risk/exposure category; (iii) clinical: AIDS-defining illness, signs and symptoms of anxiety and depression, self-reported comorbidities or coinfections; (iv) HAART-related: type of regimen, adverse reactions, number of adverse reactions, self-perception about the difficulty of treatment, time on HAART; (v) laboratory tests: CD4+ T lymphocyte count (LT-CD4+) and viral load at the beginning of HAART usage; (vi) service-related: health care unit and counseling of health professionals about HAART and (vii) quality of life.
The economy class classification was evaluated according to the Brazilian Association of Research Companies (ABEP) 13. Data for concurrent AIDS-defining illness was obtained from patient’s
clini-cal chart and classified according to the Centers for Disease Control and Prevention definition 14.
Signs and symptoms of anxiety and depression were evaluated by the Hospital Anxiety and Depression
Scale 15,16, with scores ranging from 0 to 14, and a cut off of ≥ 8 points for both anxiety and depression.
The HAART regimen was classified as STR (TDF/3TC/EFV one tablet once-daily), MTR-DTG once-daily (TDF/3TC + DTG once-daily) or other multiple tablet regimens (MTR-other), corre-sponding to all other multi-tablet multi-dose HAART regimens.
Self-perception about difficulty with treatment was measured by the following question: “Based on your experience with antiretroviral drugs so far, how would you rate your treatment on a daily basis?”. Valid options of response were dichotomized as “difficult” (very difficult, difficult, medium) or “easy” (easy, very easy).
LT-CD4+ and viral load at the beginning of the treatment were retrieved from SISCEL with a tolerance of three months. Quality of life was assessed by the WHOQOL-HIV BREF instrument, with scores ranging from 0 to 20 for each one of the six domains 17,18.
The interviews were typed into Epi Info 3.5.4 software (https://www.cdc.gov/epiinfo/index.html) and 10% of the sample was retyped for quality control, achieving a perfect inter-examiner agreement (kappa statistic = 0.95) 19.
Statistical analysis
For analytic purposes, patients were compared according to the HAART regimen in use at the time of the interview: STR, MTR-DTG or MTR-other. A descriptive analysis was carried out followed by a bivariate analysis, stratified by type of regimen. The individual association of each categorical variable with adhesion was assessed by Pearson’s chi-square test or Fischer’s exact test, when appropriate. For continuous variables, the t-test was used.
Multivariate analysis was performed through a logistic regression model and values were pre-sented by odds ratio (OR) with their respective 95% confidence intervals (95%CI). Variables with a p-value ≤ 0.20 in the bivariate analysis were selected to enter the initial multivariate model. The back-ward stepwise method was conducted until the final model contained only relevant variables (p ≤ 0,05 or with theoretical relevance). The suitability of the model was assessed by the Hosmer-Lemeshow test and by the area under the Receiver Operating Characteristics (ROC) curve, with p-values > 0.05 indicating a good fit of the model in the first test and values > 0.7 in the second one.
Statistical analyses were performed using the SPSS v. 24 (https://www.ibm.com/) at a significance level of 5% and forest plots were developed using the R (http://www.r-project.org).
Results
Among 460 eligible patients identified, 427 agreed to participate in the ECOART study. Of 427 per-sons, 31 were excluded due to lack of data on adherence and 3 because they had less than seven days of treatment initiation totalizing 393 (85%) in the current analysis. There were no statistically significant differences between participants and non-participants regarding sex, age or race.
Most of the participants were male (82.4%) and the main risk/exposure category corresponded to men who have sex with men – MSM (52.1%). The majority was single, divorced or widowed (79.6%) and was working at the time of the interview (61.3%). Approximately half were under 33 years old (51.1%), belonged to the economic class C (47.1%) and 38.4% had 10 to 12 years of schooling. A high proportion of patients consumed alcohol (79.6%) and used illicit drugs in the lifetime (49.7%). AIDS-defining illness occurred on 20% of participants and comorbidities were reported by 19.8% and 21.4% had signs and symptoms of depression and 31.3% of anxiety (Table 1).
Most patients used a therapeutic regimen containing 2 NRTIs + 1 NNRTI (66.7%), being TDF, 3TC, EFV the most common. STR was used by 254 (64.6%) patients, 106 (27%) used MTR-DTG regi-men and 33 (8.4%) used MTR-other. Approximately 70.3% considered the treatregi-ment easy and 54.7% were on HAART for more than 60 days at the time of the interview. Of the total number of patients, 85.9% had at least one and 72.6% up to five adverse reactions.
Initial LT-CD4+ count ≤ 200cells/mm3 was observed for 27% of patients and 26.5% started
HAART with viral load greater than 100,000 copies/mL. Most patients (41.7%) attended service II and approximately 12% did not receive or did not understand the health professional counseling about HAART. Mean quality of life was higher than 14.0 in all domains, with the lowest value observed in the environment domain (14.32; SD = 2.40) and the highest in the physical domain (15.44; SD = 3.09) (Table 1).
Adherence assessment
Table 2 shows patient’s responses to individual questions of the MMAS-8, where 97.7% of the patients did not take their HAART medicines because they felt better and thought the disease was under control (item 6). There was a higher frequency of responses indicating adherence among the MTR-DTG group (five items) and a lower frequency in the MTR-other group (only one item). The overall prevalence of adherence was 44.8% (n = 176) and MTR-DTG group presented the highest percentage of adherent individuals (50%), followed by the STR group (43.3%) and the MTR-other group (39.4%). However, there was no statistically significant difference between adherence to HAART among the groups and the three participanting services (p = 0.81).
The adherence to HAART in the overall population ranged from 28.6% to 61.8% according to their characteristics. Lower point estimates were observed for patients with signs and symptoms of depression (28.6%), patients who did not receive or understand health professional counseling about HAART (31.3%), patients who perceived their treatment as difficult (31.9%), patients reporting more than five adverse reactions (32.7%), those using 2 NRTI + 2 PI (33.3%) and who had used illicit drugs in the lifetime (37.4%). Higher adherence estimates were observed for individuals who did not have any adverse reaction (61.8%), were married or in a stable union (52.5%), who did not use illicit drugs in the lifetime (52.3%), aged 33 years or more (51%) and with 13+ years of schooling (47.6%) (Table 3).
Table 1
Characteristics of individuals living with HIV, according to the antiretroviral regimen used. Belo Horizonte, Minas Gerais State, Brazil, 2017 (n = 393).
Characteristics Global (n = 393) STR (n = 254) MTR-DTG (n = 106) MTR-other (n = 33) p-value
Sociodemographic
Sex (male) 323 (82.4) 209 (82.3) 90 (85.7) 24 (72.7) 0.23 Age (> 33 years) 192 (48.9) 117 (46.1) 50 (47.2) 25 (75.8) 0.01 *
Schooling level (years) 0.09 *
≤ 9 95 (24.2) 61 (24.0) 19 (17.9) 15 (45.5) 10-12 151 (38.4) 104 (40.9) 37 (34.9) 10 (30.3) 13+ 147 (37.4) 89 (35.0) 50 (47.2) 8 (24.2)
Own income in the last 6 months (yes) 324 (82.7) 211 (83.4) 88 (83.0) 25 (75.8) 0.55 Employment status (working) 241 (61.3) 165 (65.0) 62 (58.5) 14 (42.4) 0.03 *
Economic class 0.02 *
A-B 140 (36.5) 95 (38.5) 38 (35.8) 7 (22.6)
C 181 (47.1) 109 (44.1) 58 (54.7) 14 (45.2)
D-E 63 (16.4) 43 (17.4) 10 (9.4) 10 (32.3)
Marital status (married/stable union) 80 (20.4) 51 (20.1) 17 (16.0) 12 (36.4) 0.04 *
Behavioral and habits of life
Ever used alcohol (yes) 313 (79.6) 207 (81.5) 82 (77.4) 24 (72.7) 0.40 Currently smoker (yes) 102 (26.0) 66 (26.0) 29 (27.4) 7 (21.2) 0.78 Ever used any illicit drug (yes) 195 (49.7) 123 (48.4) 60 (56.6) 12 (37.5) 0.13 Condom use in all sexual intercourses in the last
month (yes)
222 (70.3) 141 (67.1) 64 (76.2) 17 (77.3) 0.23 Risk/Exposure category (MSM) 198 (52.1) 134 (54.3) 52 (51.5) 12 (37.5) 0.20
Clinical
AIDS defining illness (AIDS) 76 (20.0) 57 (23.1) 6 (5.9) 13 (40.6) < 0.01 * Anxiety (yes) 123 (31.3) 81 (31.9) 28 (26.4) 14 (42.4) 0.21 Depression (yes) 84 (21.4) 59 (23.2) 15 (14.2) 10 (33.3) 0.07 Comorbidities (yes) 78 (19.8) 51 (20.1) 13 (12.3) 14 (42.4) < 0.01 * Coinfections (yes) 28 (7.2) 22 (8.7) 2 (1.9) 4 (12.1) 0.04 *
HAART-related
Classical therapeutic regimen
-2 NRTI + 1 NNRTI 262 (66.7) 254 (100.0) - 8 (24.2) 2 NRTI + 1 IIN 110 (28.0) - 106 (100.0) 4 (12.1)
2 NRTI + 2 PI 21 (5.3) - - 21 (63.6)
Adverse reactions (yes) 335 (85.9) 226 (89.7) 81 (76.4) 28 (87.5) < 0.01 * Number of adverse reactions (> 5) 107 (27.4) 85 (33.7) 10 (9.4) 12 (37.5) < 0.01 * Self-perception of treatment difficulty (easy) 275 (70.3) 173 (68.7) 87 (82.1) 15 (45.5) < 0.01 * Time since treatment initiation (> 60 days) 214 (54.7) 152 (60.1) 38 (35.8) 24 (75.0) < 0.01 * Laboratory tests (before HAART)
CD4+ T lymphocyte count (≤ 200cells/mm3)
88 (27.0) 63 (30.0) 14 (15.6) 11 (42.3) 0.01 * Viral load (> 100,000 copies/mL) 87 (26.5) 60 (28.2) 15 (17.2) 12 (42.9) 0.02 *
Health service-related
Healthcare facility < 0.01 *
I 145 (36.9) 125 (49.2) 0 (0.0) 20 (60.6)
II 164 (41.7) 106 (41.7) 47 (44.3) 11 (33.3)
III 84 (21.4) 23 (9.1) 59 (55.7) 2 (6.1)
Receiving and understanding HAART counseling (Yes) 343 (87.7) 222 (88.1) 93 (87.7) 28 (84.8) 0.87
WHOQOL-HIV BREF domains [Mean (SD)]
Physical 15.44 (3.09) 15.32 (3.04) 16.12 (2.63) 14.18 (4.18) < 0.01 * Psychological 14.98 (2.83) 14.94 (2.92) 15.43 (2.27) 13.82 (3.46) 0.02 * Independence 15.43 (2.75) 15.47 (2.78) 15.66 (2.37) 14.39 (3.36) 0.07 * Social 15.20 (3.01) 15.07 (3.11) 15.72 (2.54) 14.48 (3.53) 0.08 Environment 14.32 (2.40) 14.31 (2.45) 14.51 (2.22) 13.86 (2.50) 0.40 Spiritual 14.66 (3.65) 14.34 (3.70) 15.43 (3.27) 14.69 (4.18) 0.04 * HAART: highly active antiretroviral therapy; IIN: integrase inhibitor; MSM: men who have sex with men; NNRTI: non-nucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; MTR-DTG: multi-tablet regimen once daily with dolutegravir – TDF/3TC + DTG; MTR-other: multi-tablet multi-dose; SD: standard deviation; STR: single tablet regimen – TDF/3TC/EFV.
Table 2
Individual answers to the eight items Morisky Therapeutic Adhesion Scale (MMAS-8) and summary scores, according to the antiretroviral regimen used. Belo Horizonte, Minas Gerais State, Brazil, 2017 (n = 393).
MMAS-8 items * Global (n = 393) STR (n = 254) MTR-DTG (n = 106) MTR-other (n = 33)
n (%) n (%) n (%) n (%)
1. Do you sometimes forget to take your medicine? (no) 311 (79.1) 202 (79.5) 84 (79.2) 25 (75.8) 2. Thinking over the past 2 weeks, were there any days
when you did not take your medicine? (no)
328 (83.5) 209 (82.3) 95 (89.6) 24 (72.7) 3. Have you ever cut back or stopped taking your
medicine without telling your doctor because you felt worse when you took it? (no)
375 (95.4) 240 (94.5) 106 (100.0) 29 (87.9)
4. When you travel or leave home, do you sometimes forget to bring along your medicine? (no)
361 (91.9) 229 (90.2) 100 (94.3) 32 (97.0) 5. Did you take all your medicines yesterday? (yes) 355 (90.3) 225 (88.6) 103 (97.2) 27 (81.8) 6. When you feel like your symptoms are under control,
do you sometimes stop taking your medicine? (no)
384 (97.7) 247 (97.2) 106 (100.0) 31 (93.9) 7. Do you ever feel hassled about sticking to your
treatment plan? (no)
317 (80.7) 202 (79.5) 92 (86.8) 23 (69.7) 8. How often do you have difficulty remembering to take
all your medicine? (never)
258 (65.6) 170 (66.9) 64 (60.4) 24 (72.7) Adherence prevalence [95%CI] 176 (44.8)
[39.4; 50.1] 110 (43.3) [36.9; 49.4] 53 (50.0) [40.4; 59.6] 13 (39.4) [22.2; 57.9] 95%CI: 95% confidence interval; MTR-DTG: multi-tablet regimen once daily with dolutegravir – TDF/3TC + DTG; MTR-other: multi-tablet multi-dose; STR: single tablet regimen – TDF/3TC/EFV.
* Use of the MMAS is protected by U.S. Copyright Laws. Permission for use is required. A license agreement is available from MMAS Research LLC 14725 NE 20th St. Bellevue WA 98007 or from dmorisky@gmail.com.
Additionally, the estimates of the prevalence of adherence to HAART according to the character-istics of the populations within the STR, MTR-DTG and MTR-other subgroups followed the same trend of the overall population, with few exceptions (Table 3).
Multivariate analysis
Figure 1 shows the results of the multivariate modeling conducted to compare the chance of adher-ence according to the potential explanatory factors. For the overall sample, the use of HAART regi-mens containing MTR-DTG (p = 0.01), receiving and understanding counseling about HAART (p = 0.03) and the physical and social domains of quality of life (p < 0.04) were associated with higher chance of HAART adherence, while the use of illicit drugs at the lifetime (p < 0.01) was associated with a lower chance. In addition, the presence of AIDS-defining symptoms showed a trend to be associated with higher adherence (p = 0.05) (Figure 1a).
Multivariate analysis restricted to the STR subgroup showed self-perception of treatment as easy (p = 0.04), receiving and understanding counseling about HAART (p = 0.04), and the social domain of quality of life (p = 0.04) were associated with higher chance of adherence, while having used illicit drugs at lifetime (p = 0.01) and occurrence of adverse reactions (p = 0.07) were associated with lower chance, although the adverse reactions results were not statistically significant (Figure 1b). For the MTR-DTG and MTR-other subgroups, quality of life domains were associated with higher chance of HAART adherence: the physical domain (p = 0.01) for individuals in the MTR-DTG group and the psychological domain (p = 0.03) for individuals in the MTR-other group (Figure 1c and 1d). In addi-tion, being employed (0.07) and the presence of AIDS-defining symptoms (p = 0.09) showed a trend to be associated with a higher adherence chance among the MTR-DTG group (Figure 1c).
Table 3
Prevalence of adherence to highly active antiretroviral therapy (HAART), according to the antiretroviral regimen used and other characteristics of individuals living with HIV. Belo Horizonte, Minas Gerais State, Brazil, 2017 (n = 393).
Characteristics Global (n = 393) STR (n = 254) MTR-DTG (n = 106) MTR-other (n = 33)
n (%) 95%CI n (%) 95%CI n (%) 95%CI n (%) 95%CI
Sociodemographic Sex Male 145 (44.9) 39.4; 50.5 93 (44.5) 37.6; 51.5 43 (47.8) 37.1; 58.6 9 (37.5) 18.8; 59.4 Female 30 (43.5) 31.6; 56.0 17 (37.8) 23.8; 53.5 9 (60.0) 32.3; 83.7 4 (44.4) 13.7; 78.8 Age (years) ≤ 33 78 (38.8) 32.0; 45.9 52 (38.0) 29.8; 46.6 25 (44.6) 31.3; 58.5 1 (12.5) 0.3; 52.7 > 33 98 (51.0) 43.7; 58.3 58 (49.6) 40.2; 59.0 28 (56.0) 41.3; 70.0 12 (48.0) 27.8; 68.7 Schooling level (years)
≤ 9 40 (42.1) 32.0; 52.7 24 (39.3) 27.1; 52.7 9 (47.4) 24.4; 71.1 7 (46.7) 21.3; 73.4 10-12 66 (43.7) 35.7; 52.0 45 (43.3) 33.6; 53.3 19 (51.4) 34.4; 68.1 2 (20.0) 2.5; 55.6 13+ 70 (47.6) 39.3; 56.0 41 (46.1) 35.4; 57.0 25 (50.0) 35.5; 64.5 4 (50.0) 15.7; 84.3 Own income in the last
6 months Yes 146 (45.1) 39.6; 50.7 92 (43.6) 36.8; 50.6 44 (50.0) 39.1; 60.9 10 (40.0) 21.1; 61.3 No 29 (42.6) 30.7; 55.2 17 (40.5) 25.6; 56.7 9 (50.0) 26.0; 74.0 3 (37.5) 8.5; 75.5 Employment status Working 115 (47.7) 41.3; 54.2 72 (43.6) 35.9; 51.6 36 (58.1) 44.8; 70.5 7 (50.0) 23.0; 77.0 Not working 61 (40.1) 32.3; 48.4 38 (42.7) 32.3; 53.6 17 (38.6) 24.4; 54.5 6 (31.6) 12.6; 56.6 Economic class A-B 64 (45.7) 37.3; 54.3 42 (44.2) 34.0; 54.8 20 (52.6) 35.8; 69.0 2 (28.6) 3.7; 71.0 C 88 (48.6) 41.1; 56.1 51 (46.8) 37.2; 56.6 29 (50.0) 36.6; 63.4 8 (57.1) 28.9; 82.3 D-E 21 (33.3) 22.0; 46.3 14 (32.6) 19.1; 48.5 4 (40.0) 12.2; 73.8 3 (30.0) 6.7; 65.2 Marital status Single/Divorced/ Widowed 134 (42.8) 37.3; 48.5 84 (41.4) 34.5; 48.5 41 (46.1) 35.4; 57.0 9 (42.9) 21.8; 66.0 Married/Stable union 42 (52.5) 41.0; 63.8 26 (51.0) 36.6; 65.2 12 (70.6) 44.0; 89.7 4 (33.3) 9.9; 65.1 Behavioral and habits of life Alcohol use Yes 137 (43.8) 38.2; 49.5 89 (43.0) 36.2; 50.0 40 (48.8) 37.6; 60.1 8 (33.3) 15.6; 55.3 No 39 (48.8) 37.4; 60.2 21 (44.7) 30.2; 59.9 13 (54.2) 32.8; 74.4 5 (55.6) 21.2; 86.3 Currently smoker Yes 42 (41.2) 31.5; 51.4 25 (37.9) 26.2; 50.7 15 (51.7) 32.5; 70.6 2 (28.6) 3.7; 71.0 No 134 (46.0) 40.2; 52.0 85 (45.2) 38.0; 52.6 38 (49.4) 37.8; 61.0 11 (42.3) 23.4; 63.1 Ever used any illicit
drug Yes 73 (37.4) 30.6; 44.6 42 (34.1) 25.8; 43.2 27 (45.0) 32.1; 58.4 4 (33.3) 9.9; 65.1 No 103 (52.3) 45.1; 59.4 68 (51.9) 43.0; 60.7 26 (56.5) 41.1; 71.1 9 (45.0) 23.1; 68.5 Condom use Yes 95 (42.8) 36.2; 49.6 56 (39.7) 31.6; 48.3 32 (50.0) 37.2; 62.8 7 (41.2) 18.4; 67.1 No 43 (45.7) 35.4; 56.3 31 (44.9) 32.9; 57.4 11 (55.0) 31.5; 76.9 1 (20.0) 0.5; 71.6 Risk/Exposure category MSM 90 (45.5) 38.4; 52.7 59 (44.0) 35.5; 52.9 25 (48.1) 34.0; 62.4 6 (50.0) 21.1; 78.9 Other 81 (44.5) 37.2; 52.0 47 (41.6) 32.4; 51.2 27 (55.1) 40.2; 69.3 7 (35.0) 15.4; 59.2 (continues)
Table 3 (continued) Characteristics Global (n = 393) STR (n = 254) MTR-DTG (n = 106) MTR-other (n = 33)
n (%) 95%CI n (%) 95%CI n (%) 95%CI n (%) 95%CI
Clinical
AIDS defining illness
Non-AIDS 131 (43.1) 37.5; 48.9 78 (41.1) 34.0; 48.4 47 (49.5) 39.1; 59.9 6 (31.6) 12.6; 56.6 AIDS 40 (52.6) 40.8; 64.2 28 (49.1) 35.6; 62.7 5 (83.3) 35.9; 99.6 7 (53.8) 25.1; 80.8 Anxiety Yes 48 (39.0) 30.4; 48.2 31 (38.3) 27.7; 49.7 14 (50.0) 30.6; 69.4 3 (21.4) 4.7; 50.8 No 128 (47.4) 41.3; 53.5 79 (45.7) 38.1; 53.4 39 (50.0) 38.5; 61.5 10 (52.6) 28.9; 75.6 Depression Yes 24 (28.6) 19.2; 39.5 17 (28.8) 17.8; 42.1 5 (33.3) 11.8; 61.6 2 (20.0) 2.5; 55.6 No 152 (49.2) 43.5; 54.9 93 (47.7) 40.5; 54.9 48 (52.7) 42.0; 63.3 11 (47.8) 26.8; 69.4 Comorbidities Yes 35 (44.9) 33.6; 56.6 24 (47.1) 32.9; 61.5 8 (61.5) 31.6; 86.1 3 (21.4) 4.7; 50.8 No 141 (44.8) 39.2; 50.4 86 (42.4) 35.5; 49.5 45 (48.4) 37.9; 59.0 10 (52.6) 28.9; 75.6 Coinfections Yes 13 (46.4) 27.5; 66.1 11 (50.0) 28.2; 71.8 2 (100.0) 100.0; 100.0 0 (0.0) 0.0; 60.2 No 162 (44.6) 39.5; 49.9 98 (42.6) 36.1; 49.3 51 (49.0) 39.1; 59.0 13 (44.8) 26.4; 64.3 HAART-related Classical therapeutic regimen 2 NRTI + 1 NNRTI 115 (43.9) 37.8; 50.1 110 (43.3) 37.1; 49.6 * * 5 (62.5) 24.5; 91.5 2 NRTI + 1 IIN 54 (49.1) 39.4; 58.8 - - 53 (50.0) 40.1; 59.9 1 (25.0) 0.6; 80.6 2 NRTI + 2 PI 7 (33.3) 14.6; 57.0 - - * * 7 (33.3) 14.6; 57.0 Adverse reactions Yes 141 (42.1) 36.8; 47.6 92 (40.7) 34.2; 47.4 40 (49.4) 38.1; 60.7 9 (32.1) 15.9; 52.4 No 34 (61.8) 47.7; 74.6 17 (65.4) 44.3; 82.8 13 (52.0) 31.3; 72.2 4 (100.0) 100.0; 100.0 Number of adverse reactions ≤ 5 140 (49.5) 43.5; 55.5 81 (48.5) 40.7; 56.3 49 (51.0) 40.6; 61.4 10 (50.0) 27.2; 72.8 > 5 35 (32.7) 24.0; 42.5 28 (32.9) 23.1; 44.0 4 (40.0) 12.2; 73.8 3 (25.0) 5.5; 57.2 Self-perception of treatment difficulty Easy 139 (50.5) 44.5; 56.6 87 (50.3) 42.6; 58.0 44 (50.6) 39.6; 61.5 8 (53.3) 26.6; 78.7 Difíccult 37 (31.9) 23.6; 41.2 23 (29.1) 19.4; 40.4 9 (47.4) 24.4; 71.1 5 (27.8) 9.7; 53.5 Time on HAART (days)
≤ 60 87 (49.2) 41.6; 56.8 46 (45.5) 35.6; 55.8 37 (54.4) 41.9; 66.5 4 (50.0) 15.7; 84.3 > 60 89 (41.6) 34.9; 48.5 64 (42.1) 34.2; 50.4 16 (42.1) 26.3; 59.2 9 (37.5) 18.8; 59.4 Laboratorial (before HAART) CD4+ T lymphocyte count (cells/mm3) ≤ 200 44 (50.0) 39.1; 60.9 34 (54.0) 40.9; 66.6 7 (50.0) 23.0; 77.0 3 (27.3) 6.0; 61.0 > 200 99 (41.6) 35.3; 48.1 58 (39.5) 31.5; 47.8 36 (47.4) 35.8; 59.2 5 (33.3) 11.8; 61.6 Viral load (copies/mL)
≤ 100,000 105 (43.6) 37.2; 50.1 67 (43.8) 35.8; 52.0 33 (45.8) 34.0; 58.0 5 (31.3) 11.0; 58.7 > 100,000 40 (46.0) 35.2; 57.0 27 (45.0) 32.1; 58.4 8 (53.3) 26.6; 78.7 5 (41.7) 15.2; 72.3 (continues)
Table 3 (continued) Characteristics Global (n = 393) STR (n = 254) MTR-DTG (n = 106) MTR-other (n = 33)
n (%) 95%CI n (%) 95%CI n (%) 95%CI n (%) 95%CI
Health service- related Healthcare facility I 68 (46.9) 38.6; 55.4 59 (47.2) 38.2; 56.3 0 (0.0) * 9 (45.0) 23.1; 68.5 II 71 (43.3) 35.6; 51.2 43 (40.6) 31.1; 50.5 25 (53.2) 38.1; 67.9 3 (27.3) 6.0; 61.0 III 37 (44.0) 33.2; 55.3 8 (34.8) 16.4; 57.3 28 (47.5) 34.3; 60.9 1 (50.0) 1.3; 98.7 Receiving and understanding HAART counseling Yes 160 (46.6) 41.3; 52.1 103 (46.4) 39.7; 53.2 45 (48.4) 37.9; 59.0 12(42.9) 24.5; 62.8 No 15 (31.3) 18.7; 46.3 6 (20.0) 7.7; 38.6 8 (61.5) 31.6; 86.1 1 (20.0) 0.5; 71.6 95%CI: 95% confidence interval; HAART: highly active antiretroviral therapy; IIN: integrase inhibitor; MSM: men who have sex with men; NNRTI: non-nucleoside reverse transcriptase inhibitor; NRTI: non-nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; MTR-DTG: multi-tablet regimen once daily with dolutegravir – TDF/3TC + DTG; MTR-other: multi-tablet multi-dose; STR: single tablet regimen – TDF/3TC/EFV.
* Not estimable.
All models presented a good fit, with Hosmer-Lemeshow test and the ROC curve values lower than 0.05 and higher than 0.7, respectively. Specific values were p = 0.17 and ROC = 0.7 for the global model, p = 0.55 and ROC = 0.7 for STR model, p = 0.48 and ROC = 0.7 for MTR-DTG model and p = 0.41 and ROC = 0.8 for the MTR-other model.
Discussion
In this cross-sectional study, which included individuals at the beginning of treatment, the overall rate of adherence was 44.8%, measured by the MMAS-8 self-report scale. Despite having no differences between the HAART subgroups in the raw analysis, multivariate modeling showed a higher chance of adherence among patients using the multi-table once-daily regimen containing TDF/3TC + DTG. In addition, different factors influenced the adherence in each subgroup.
Regarding the characteristics of the sample, there was a predominance of males, MSM, aged less than 33 years, with 10 to 12 years of schooling, with their own income in the last six months, employed and single, divorced or widowed. These results are consistent with the profile of the Bra-zilian people living with HIV and the trend of increase of the HIV epidemic among young MSM 6,20.
The overall prevalence of adherence observed in the present study was similar to the ones report-ed in Brazil in earlier years 21,22 and worldwide 23,24,25. Previous studies using the MMAS-8 with the
same cut-off point as ours reported a prevalence of adherence of 43.7% 24 and 61.7% 25, while studies
using other self-report measurements of adherence reported rates above 70% 3,26,27.
The rate of adherent individuals within the HAART subgroups was lower in the present study when compared to the literature. Studies using self-report scales showed rates of adhesion ranging from 62% to 85.4% for the STR group and from 48.6% to 92.8% for MTR groups 26,27. However, when
a higher cut-off point in the MMAS-8 is used (100%), reported rates can be as lower as 14.2% for STR and 26.9% for MTR 23.
Studies evaluating adherence specifically in MTR-DTG regimens are scarce, and those evaluating HAART regimens of multi-tablet once-daily also reported higher rates of adherent individuals than our study: 65.3% 28 and 68.9% 7. However, they measured adherence using pharmacy refill records
and tablet counts, respectively.
There are plenty of methods to measure adherence and the differences between them impact on the results and its comparability across studies. Indirect methods, like self-report, can be measured
Figure 1
Forest plot of multivariate analysis of adherence to highly active antiretroviral therapy (HAART) according to the antiretroviral regimen.
(continues)
by direct questions to patients or using scales, such as the MMAS-8, the Visual Analogue Scale and the
Questionnaire for the Evaluation of Adherence to Antiretroviral Treatment. Another issue is related to the
cut-off points adopted to define adherence. Most studies use a cut-off point up to 95%, while in the present study a more rigorous cut-off point was adopted (100%). Additionally, the specificity of the Brazilian therapeutic regimens, as well as the cultural and sociodemographic characteristics of the population, can explain the variability in the results.
The overall adherence to antiretroviral therapy was influenced by behavioral and lifestyle habits, clinical, HAART and health service-related characteristics and by the quality of life. Garbin et al. 29
found in a literature review a rate of adherence to antiretroviral therapy ranged from 18% to 74.3% among Brazilian states.
There are several studies in the literature reporting better adherence rates among patients using STR when compared to multi-dose MTR 7,8,28,30. The meta-analysis of Nachega et al. 8 showed
bet-ter adherence for HAART-naïve patients using once-daily regimens, which included STR and other regimens taken once-daily in the same group, compared to twice-daily regimens. Results for the com-parison of STR to once-daily MTR, however, are more heterogeneous, with studies reporting better results to STR or absence of difference among groups 7,28.
Contrastingly, in our study, the MTR once-daily containing DTG showed better results when compared to the STR. Both regimens are used with the “backbone” of TDF/3TC, and bottom line, the comparison of effects are related to the third antiretroviral agent characteristics, such as their pill burden and tolerability. We observed a lower rate of adverse events and a lower proportion of patients
Figure 1 (continued)
95%CI: 95% confidence interval; MTR-DTG: multi-tablet regimen once daily with dolutegravir – TDF/3TC + DTG; MTR-other: multi-tablet multi-dose; OR: odds ratio; STR: single tablet regimen – TDF/3TC/EFV.
having more than five adverse drug reactions among patients in the MTR-DTG group. The profile of adverse events also differenced among groups 31 and may have contributed to increasing the chance of adherence to HAART. Adverse reactions such as dizziness, rashes, and vomiting are common and may interfere negatively with the patient’s daily life. Discussing all possible adverse reactions before start-ing HAART and managstart-ing the symptoms are critical for achievstart-ing a good adherence. Additionally, individual evaluation of adverse reactions can be useful in the elaboration of strategies to maintain a good adherence 32.
The association between quality of life and adherence is common in the literature, and studies have reported a higher quality of life and its components, such as the capacity of working, social support and psychological status to influence the success of HAART 33. In our study, patients on MTR-other
regimens showed, in general, a worse prognosis compared to other groups, illustrated by the higher rate of advanced disease, a higher number of comorbidities and higher adverse events rate. In addition to lower adherence rates, all these characteristics may affect their social role and self-perception on their health status, reflecting the lower quality of life values among this group.
The quality of the counseling to the patient about their HAART treatment and the good relation-ship between patient and health professionals also influenced positively the adherence 24,34. The
counseling about medicines help the individual to better understand his/her treatment and this contributes for patients to strive more to follow it correctly. Indeed, individual’s perception of their treatment as easy was associated with higher chance of adherence to HAART in the STR subgroup. Previous studies have shown individuals who considered their treatment difficult were 21 times more likely to have inadequate adherence 35.
Another concern is with the use of illicit drugs, as they affected negatively the adherence to HAART in this and in several other studies 27,32. Some possible strategies to increase adherence
include treating the addiction, preparing health professionals to deal with these individuals, and seek-ing healthier alternatives for copseek-ing together with patients 36,37. Therefore, investing in strategies to
improve and broaden the counseling by health professionals is of great importance, since this type of strategy can target simultaneously various factors related to adherence, has low cost, easy implemen-tation and results are achieved in the short to medium term. In addition, health professionals should individually approach patient’s self-perception in order to clarify possible doubts and improve their own perception 35.
Low adherence to HAART is a public health issue, as it influences not only the health of each individual but also the overall population living with HIV. In addition to being a major cause of therapeutic failure, it increases the risk of developing drug resistance. The transmission of resistant strains to the initial therapeutic regimens contributes to the bankruptcy of these regimens, leading to negative impacts on public policies and on the health system 38. Clinically, one of the outcomes of
inadequate adherence is the reduction of LT-CD4+ leading to a decreased immunity level, increased risk of opportunistic infections, and possible progression to AIDS. These factors may also result in an increase in the risk of hospitalizations and consequently higher costs to the health system 38,39.
Strategies to achieve adequate HAART adherence include cognitive-behavioral therapy, per-formed in motivational interviews and followed by educational actions, choice of supporters and medicines reminder devices, such as cell phone alarms and tablet packaging with timers or alarms 40.
Short message service, such as SMS text messaging, also increase adherence compared to standard care and combined interventions resulted in greater overall adherence than isolated interventions 41.
Despite the adherence results, a study with participants of service I showed, at six months, 74.6% of overall viral suppression and 80.6% of viral supression among patients who used STR (p = 0.04). Factors independently associated with viral suppression at six months were: (negatively) viral load ≥ 100,000 copies/mL, symptoms of AIDS, longer interval time between diagnosis and initiation of antiretroviral therapy, antiretroviral switching, smoking or current illicit drugs usage; and (positively) category of exposure of men who have sex with men and acherence to HAART 42.
An international cohort study in South Carolina (USA) showed that people using STR achieve viral suppression with adherence levels of 80% or greater, whereas people using MTR require adher-ence levels of 90% or greater to achieve viral suppression 43.
In Brazil, the Ministry of Health recommends the support of the multi-professional team to the individual, including the implementation of support groups, lectures, activities in waiting rooms, educational activities with the availability of material and actions in partnership with civil society organizations. Furthermore, it is important health professionals to well-inform individuals in a clear way, making sure they understand the information. In addition, it is important to understand patients’ beliefs and routines to determine together the best way to achieve adherence 4.
High-quality HIV services must continue to expand in order to maintain and improve the out-comes. Brazil has seen an increase from 83% (in 2015) to 84% (in 2017) in HIV-diagnosis. The portion of people living with HIV on treatment stood at 64% in 2017, 59% of whom were virally suppressed. One major challenge is the sustained programs in the country for reducing the number of new infec-tions among key affected populainfec-tions 4.
This study has some limitations. The adherence was measured by a self-report scale not specific to HIV. However, this method is fast, easy to apply and is a good predictor of virological failure 44.
Furthermore, several studies used the MMAS-8 to measure HAART adherence 23,24,25,35 and although
there is a multiplicity of indirect measures of adherence, none of them is considered a “gold stan-dard”. The triangulation of methods increases the validity and reliability of the adherence results. For greater robustness of results and to allow comparisons between them, future research and practice interventions should use a standardized and internationally accepted definition; clearly describing which medicines and methods were used.
In addition, due to the cross-sectional design of the study, it is not possible to establish the tem-poral relationship between cause and effect. However, we continue to follow up patients to evaluate long-term results and to confirm these findings. Finally, the study’s population was selected by non-randomized sampling although we have universal register on the SICLOM.
Conclusion
The overall adherence rate in individual’s initiating HAART was low with better results for patients using the dolutegravir once-daily regimen, which is the first-choice regimen currently used in Brazil. Results highlighted the need for intervention strategies to increase adherence to HAART, focusing on health professional’s counseling about HAART and substance use. Finally, the interventions per-formed should be specific and oriented to the HAART-regimen, since different factors affect adher-ence in each group.
Contributors
T. S. Cardoso was responsible for study design, data extraction, data interpretation, drafting of the manuscript and approval of the final manuscript. J. O. Costa was responsible for data extraction, data analyses, data interpretation, drafting of the manu-script and critical review. E. A. Reis was responsible for data interpretation, critical review, and approval of the final manuscript. M. R. Silveira was respon-sible for study design, critical review, and approval of the final manuscript. P. F. Bonolo was responsible for study design, data interpretation, and critical review. S. F. Santos was responsible for data inter-pretation and critical review. M. G. B. Ceccato was responsible for study design, data analyses, data interpretation, critical review, and approval of the final manuscript.
Additional informations
ORCID: Tarsilla Spezialli Cardoso 8400-1689); Juliana de Oliveira Costa (0000-0002-8355-023X); Edna Afonso Reis (0000-0003-1465-9167); Micheline Rosa Silveira (0000-0001-7002-4428); Palmira De Fátima Bonolo 0003-2744-7139); Simone Furtado Dos Santos (0000-0002-2060-5934); Maria das Graças Braga Ceccato (0000-0002-4340-0659).
Acknowledgments
Use of the MMAS is protected by U.S. Copyright Laws. Permission for use is required. A license agree-ment is available from MMAS Research LLC 14725 NE 20th St. Bellevue WA 98007 or from dmorisky@ gmail.com. To Minas Gerais State Research Founda-tion (FAPEMIG) for the financial support.
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Resumo
Avaliamos a adesão à terapia antirretroviral (TARV) e fatores associados de acordo com o tipo de esquema em pacientes no início do tratamento em Belo Horizonte, Minas Gerais, Brasil. Mensu-ramos a adesão com a Escala de Adesão
Tera-pêutica de Morisky, de oito itens (MMAS-8), e
comparamos o uso de tenofovir/lamivudina com efavirenz, um comprimido uma vez ao dia (STR), ou dolutegravir em múltiplos comprimidos uma vez ao dia (MTR-DTG), com outros esquemas com múltiplos comprimidos ao dia (MTR-outros). Conduzimos uma análise de regressão logística multivariada para avaliar os fatores associados à adesão. Foram incluídos 393 pacientes: 254 em uso de STR, 106 MTR-DTG e 33 MTR-outros. A ta-xa global de adesão foi 44,8% (IC95%: 39,4; 50,1), sendo 50% para MTR-DTG, 43,3% para STR e 39,4% para MTR-outros. A análise multivariada mostrou chances maiores de adesão em pacientes em uso de MTR-DTG, pacientes que haviam re-cebido e compreendido o aconselhamento sobre o tratamento e pacientes com melhor qualidade de vida. Uso anterior de drogas ilícitas em qualquer período da vida está associada à pior adesão. A adesão global foi baixa, enfatizando a necessida-de necessida-de estratégias focadas no aconselhamento sobre medicamentos e uso de drogas. A quantidade de comprimidos não foi um problema para pacientes em uso de MTR-DTG uma vez ao dia, os quais alcançaram melhores taxas de adesão.
HIV; Antirretrovirais; Adesão à Medicação; Autorrelato
Resumen
Evaluamos la adherencia a la terapia antirretrovi-ral altamente activa (TARAA) y sus factores aso-ciados, según el tipo de tratamiento en pacientes que comenzaron su tratamiento en Belo Horizonte, Minas Gerais, Brasil. La adherencia se mensu-ró por la Escala de Adhesión Terapéutica de
Morisky, de ocho ítems (MMAS-8), y se comparó
el uso del “eje” tenofovir/lamivudina, además de un comprimido de efavirenz una vez al día (STR) o dolutegravir con varios comprimidos una vez al día (MTR-DTG), u otros tratamientos con múl-tiples comprimidos (MTR-otros). Se realizó un análisis multivariado de regresión logística para evaluar los factores asociados a la adherencia. Se incluyeron un total de 393 pacientes, 254 usaron STR, 106 MTR-DTG, y 33 MTR-Otros. La tasa de adherencia general fue de un 44,8% (95%CI: 39,4; 50,1), 50% en el MTR-DTG, 43,3% en el STR y 39,4% en el MTR-otros. El análisis multi-variado mostró una probabilidad más alta de ad-herencia entre pacientes usando MTR-DTG, quie-nes recibieron y comprendieron las orientacioquie-nes acerca de sus tratamientos y los que disfrutaban de una calidad mejor de vida. El consumo previo de drogas ilícitas a lo largo de la vida estuvo asociado con una adherencia más escasa. La adherencia ge-neral fue baja y resalta la necesidad de estrategias que se enfoquen en brindar orientación sobre el uso de la medicación y de sustancias. El número de comprimidos no fue un problema para los pacien-tes que tomaban MTR-DTG una vez al día, que obtuvieron mejores resultados.
VIH; Antirretrovirales; Cumplimiento de la Medicación; Autoinforme
Submitted on 12/Jun/2018
Final version resubmitted on 25/Jan/2019 Approved on 05/Apr/2019
